On December 10, 2022 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported data from the safety lead-in portion of its ongoing SELECT-AML-1 Phase 2 trial evaluating tamibarotene, an oral, selective retinoic acid receptor alpha (RARα) agonist, in combination with venetoclax and azacitidine in newly diagnosed, unfit patients with acute myeloid leukemia (AML) and RARA gene overexpression (Press release, Syros Pharmaceuticals, DEC 10, 2022, View Source [SID1234625061]). The data is being presented today in a poster session at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place in New Orleans, LA.

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"As a physician devoted to the care and treatment of leukemia, I am reminded daily of the limitations of existing therapeutic options, with approximately one-third of unfit AML patients failing to respond in the frontline setting and nearly all relapsing over time," said Daniel Pollyea, M.D., M.S., Professor of Medicine and Clinical Director of Leukemia Services at the University of Colorado School of Medicine. "These data provide early evidence that tamibarotene can be combined with the existing standard-of-care to deliver improved outcomes to the approximately 30% of AML patients who are positive for RARA overexpression – many of whom present with a disease phenotype associated with features of venetoclax resistance. I look forward to enrolling patients in the randomized portion of the Phase 2 trial and to further characterizing the potential of tamibarotene as a novel combination agent for use in patients with hematologic malignancies."

"We are highly encouraged by the initial data from SELECT-AML-1, which address the two questions we set out to answer in the safety lead-in, demonstrating both the tolerability of tamibarotene in combination with venetoclax and azacitidine, as well as the potential clinical benefit of adding tamibarotene to existing standard-of-care," said David A. Roth, M.D., Chief Medical Officer of Syros. "In AML patients with RARA gene overexpression, the triplet regimen with tamibarotene at full dose demonstrated a high response rate and rapid onset of action, with no evidence of increased toxicities beyond what would be expected with the combination of venetoclax and azacitidine. Based on these data, we intend to move rapidly to initiate the randomized portion of our Phase 2 SELECT-AML-1 trial, while also continuing to enroll patients in SELECT-MDS-1, where we are evaluating the combination of tamibarotene with standard-of-care azacitidine in patients with higher-risk myelodysplastic syndrome and RARA gene overexpression."

Encouraging Initial Data from SELECT-AML-1 Phase 2 Trial
As of October 13, 2022, eight newly diagnosed, unfit, RARA-positive patients had been enrolled in the trial, including six who were evaluable for response. The median age of the patients was 61 (ranging from 55-82) and the median percent blasts at baseline was 63% (ranging from 39-100%).

Initial Safety Data
– Tamibarotene in combination with venetoclax and azacitidine administered at approved doses showed no evidence of increased toxicity relative to the doublet combination of venetoclax and azacitidine. This includes rates of myelosuppression, which were comparable to reports with venetoclax and azacitidine in this population.
– Serious adverse events (SAEs) were reported in all six patients. The most frequently occurring SAEs included febrile neutropenia (66%) and pneumonia (50%).
– The majority of non-hematologic AEs were low grade and reversible. The most frequently occurring non-hematologic AEs included pneumonia (66%), cough (50%), anxiety (50%), decreased appetite (50%) and rash (50%).

Initial Clinical Activity Data
– The complete response (CR) and complete response with incomplete blood count recovery (CRi) rate, as defined by Revised International Working Group (IWG) criteria was 83%, consisting of two patients (33%) who achieved a CR and three patients (50%) who achieved a CRi.
° Four of five patients (80%) who achieved a CR or CRi had a high monocytic expression score (MES), which may be associated with venetoclax resistance.1
– Median time to CR/CRi response was 33 days (ranging from 25-88).
– Median duration of treatment was 76.5 days (ranging from 20-104) and median duration of follow-up was 107 days (ranging from 56-314).
– These early data compare favorably to the standard-of-care combination of venetoclax and azacitidine, which shows composite CR rates of 66% in newly diagnosed unfit AML patients.2

Advancing Tamibarotene in Newly Diagnosed Unfit AML
Based on the encouraging data reported today, Syros plans to advance into the randomized portion of the SELECT-AML-1 Phase 2 trial, which will evaluate the safety and efficacy of tamibarotene in combination with venetoclax and azacitidine in approximately 80 patients positive for RARA overexpression randomized 1:1 to treatment with tamibarotene and venetoclax/azacitidine vs. venetoclax/azacitidine. The trial will incorporate venetoclax dose modification guidelines based on the recently published European LeukemiaNet (ELN) recommendations,3 and will also evaluate the triplet regimen as a salvage therapy in patients who do not respond to venetoclax and azacitidine in the control arm. The randomized portion is expected to initiate in Q1 2023, with data expected in 2023 or 2024.

The ASH (Free ASH Whitepaper) presentation is now available on the Publications and Abstracts section of the Syros website at www.syros.com.

Conference Call Information

Syros will host a conference call at 12:00 p.m. ET today to discuss these data, as well as review the unmet need in newly diagnosed, unfit AML. In addition to Syros management, the event will feature a presentation from Daniel Pollyea, M.D., M.S., Associate Professor of Medicine, Clinical Director of Leukemia Services, University of Colorado School of Medicine. To access the live event, please register here. In addition, a live webcast of the presentation will be available on the Investors & Media section of the Syros website at www.syros.com. An archived replay of the webcast will be available for approximately 30 days following the presentation.